To help elucidate the mechanisms for cisplatin drug resistance in the treatment of melanoma, accumulation of platinum as well as changes in subcellular ultrastructure were determined in cultured MTN-1 melanoma cells. Specimens were prepared by high-pressure freezing, low-temperature freeze-substitution in acetone, and low-temperature embedding in UV-polymerized Lowicryl resin. Unstained ultramicrotomed sections of thickness approximately 100 nanometers were imaged by transmission electron microscopy (TEM) and analyzed using electron probe x-ray microanalysis in a scanning transmission electron microscope, equipped with a field-emission source. Sections of thickness approximately 200 nanometers were also analyzed using the x-ray microprobe at the Advanced Photon Source in Argonne National Laboratory. The x-ray microprobe provides increased sensitivity for platinum detection due to its high brightness synchrotron source but gives lower spatial resolution due to limits of the zone-plate x-ray optics. Results from these complementary approaches showed that prolonged treatment with cisplatin increased the number of intracellular pigmented granules (melanosomes), and importantly revealed accumulation of platinum in the melanosomes. The findings indicate that altered response of melanosomes might contribute to cisplatin-resistance in melanoma cells.